scholarly journals Inhibition of HDAC6 Activity Alleviates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Potential Role of Peroxiredoxin 1 Acetylation and Redox Regulation

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Yan Leng ◽  
Yang Wu ◽  
Shaoqing Lei ◽  
Bin Zhou ◽  
Zhen Qiu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Protective Effect ◽  
Redox Regulation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
H9c2 Cells ◽  
Peroxiredoxin 1 ◽  
Myocardial Ischemia Reperfusion

Patients with diabetes are more vulnerable to myocardial ischemia/reperfusion (MI/R) injury, which is associated with excessive reactive oxygen species (ROS) generation and decreased antioxidant defense. Histone deacetylase 6 (HDAC6), a regulator of the antioxidant protein peroxiredoxin 1 (Prdx1), is associated with several pathological conditions in the cardiovascular system. This study investigated whether tubastatin A (TubA), a highly selective HDAC6 inhibitor, could confer a protective effect by modulating Prdx1 acetylation in a rat model of MI/R and an in vitro model of hypoxia/reoxygenation (H/R). Here, we found that diabetic hearts with excessive HDAC6 activity and decreased acetylated-Prdx1 levels were more vulnerable to MI/R injury. TubA treatment robustly improved cardiac function, reduced cardiac infarction, attenuated ROS generation, and increased acetylated-Prdx1 levels in diabetic MI/R rats. These results were further confirmed by an in vitro study using H9c2 cells. Furthermore, a study using Prdx1 acetyl-silencing mutants (K197R) showed that TubA only slightly attenuated H/R-induced cell death and ROS generation in K197R-transfected H9c2 cells exposed to high glucose (HG), but these differences were not statistically significant. Taken together, these findings suggest that HDAC6 inhibition reduces ROS generation and confers a protective effect against MI/R or H/R injury by modulating Prdx1 acetylation at K197.

scholarly journals The Protective Effect of Cyanidin-3-Glucoside on Myocardial Ischemia-Reperfusion Injury through Ferroptosis

2021 ◽  
Vol 2021 ◽  
pp. 1-15 ◽  
Author(s):  
Xin Shan ◽  
Zhi-Yang Lv ◽  
Meng-Jiao Yin ◽  
Jing Chen ◽  
Jie Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Protective Effect ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
H9c2 Cells ◽  
St Segment Elevation ◽  
Myocardial Ischemia Reperfusion

This study was conducted to estimate the protective effect of Cyanidin-3-glucoside (C3G) on myocardial ischemia-reperfusion (IR) injury and to explore its mechanism. The rats were subjected to left anterior descending ligation and perfusion surgery. In vitro experiments were performed on H9c2 cells using the oxygen-glucose deprivation/reoxygenation (OGD/R) model. The results showed the administration of C3G reduced the infarction area, mitigated pathological alterations, inhibited ST segment elevation, and attenuated oxidative stress and ferroptosis-related protein expression. C3G also suppressed the expressions of USP19, Beclin1, NCOA4, and LC3II/LC3I. In addition, treatment with C3G relieved oxidative stress, downregulated LC3II/LC3I, reduced autophagosome number, downregulated TfR1 expression, and upregulated the expressions of FTH1 and GPX4 in OGD/R-induced H9c2 cells. C3G could inhibit the protein levels of USP19 and LC3II. C3G promoted K11-linked ubiquitination of Beclin1. Further evidence that C3G reduced ferroptosis and ameliorated myocardial I/R injury was demonstrated with the ferroptosis promoter RSL3. Taken together, C3G could be a potential agent to protect myocardium from myocardial I/R injury.

scholarly journals Downregulated MicroRNA-327 Attenuates Oxidative Stress–Mediated Myocardial Ischemia Reperfusion Injury Through Regulating the FGF10/Akt/Nrf2 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Tao Zheng ◽  
Jun Yang ◽  
Jing Zhang ◽  
Chaojun Yang ◽  
Zhixing Fan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Nrf2 Signaling Pathway ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Although miR-327 had a protective effect on cardiomyocytes as described previously, the potential mechanism still needs further exploration. The aim of this study was to investigate the role and mechanism of miR-327 on oxidative stress in myocardial ischemia/reperfusion injury (MI/RI) process. Oxidative stress and cardiomyocytes injury were detected in rat model of MI/RI, hypoxia/reoxygenation (H/R), and tert-butyl hydroperoxide (TBHP) model of H9c2 cells. In vitro, downregulation of miR-327 inhibited both H/R- and TBHP-induced oxidative stress, and suppressed apoptosis. Meanwhile, fibroblast growth factor 10(FGF10) was enhanced by miR-327 knocked down, followed by the activation of p-PI3K and p-Akt, and the translocation of Nrf2. However, miR-327 overexpression performed with opposite effects. Consistent with the results in vitro, downregulation of miR-327 attenuated reactive oxygen species (ROS) generation as well as intrinsic apoptosis, and alleviated I/R injury. In conclusion, inhibition of miR-327 improved antioxidative ability and myocardial cell survival via regulating the FGF10/Akt/Nrf2 pathway.

scholarly journals Reduced β2-glycoproteinI Alleviated Rat Myocardial Ischemia/Reperfusion Injury via Mitochondrial Protection and Inhibition of Apoptosis

2020 ◽  
Author(s):  
Saijun Zhou ◽  
Zhenxing Meng ◽  
Shumin Xiao ◽  
Ting Cheng ◽  
Shuai Huang ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Myocardial Ischemia ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
H9c2 Cells ◽  
Myocardial Ischemia Reperfusion ◽  
Gsk 3Β

Abstract BackgroundMyocardial ischemia/reperfusion (I/R) injury is one of the most important reasons for death of coronary heart disease after vascular recanalization. New evidences have shown that β2-glycoprotein I (β2GPI) plays a protective role in cardiovascular diseases. This study aims to evaluate the effects of reduced β2GPI (R-β2GPI), one form of β2GPI, on myocardial I/R injury, and to explore related mechanisms. MethodsThe in vivo myocardial I/R models of Sprague Dawley rats and in vitro hypoxia/reoxygenation(H/R) models of H9c2 cells were established. The myocardial infarction and morphological changes in SD rats were measured by the TTC staining and HE staining. Creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) levels in plasma were detected by ELISA Assay kit. Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) method and caspase-3 colorimetric assay kit were used to determine myocardial apoptosis. Intracellular reactive oxygen species (ROS) generation and mitochondrial membrane potential of H9c2 cells were measured by fluorescent probe DCFH-DA and JC-1 fluorescent staining respectively. To evaluate cell damage, cell viability was assessed by determining the release of lactate dehydrogenase (LDH). The ratio of Bcl-2/Bax at mRNA level was detected by reverse transcription-polymerase chain reaction (RT-PCR). Western blot analysis was used to detect the expression levels of total Akt and phosphorylated Akt as well as the expression levels of total GSK-3βand phosphorylated GSK-3β in H9c2 cells. ResultsOur results suggested that R-β2GPI improved I/R model rats’ heart function, decreased infarct size, reduced serum CK-MB, cTnI levels, cell apoptosis and caspase3 activity. In vitro, R-β2GPI decreased LDH leakage, reduced ROS generation, maintained mitochondrial membrane potential and increased bcl-2/bax mRNA ratio; increased phosphorylation of Akt and GSK-3β in H9c2 cells following Hypoxia/Reoxygenation (H/R) jnjury. ConclusionR-β2GPI alleviated myocardial I/R (or H/R) injury by reducing oxidative stress and inhibiting mitochondrial apoptotic pathway via increasing the phosphorylation of Akt/GSK-3β.

MicroRNA-760-mediated low expression of DUSP1 impedes the protective effect of NaHS on myocardial ischemia–reperfusion injury

2020 ◽  
Vol 98 (3) ◽  
pp. 378-385
Author(s):  
Lin Ren ◽  
Qian Wang ◽  
Lixiang Ma ◽  
Dongmei Wang
Keyword(s):  
Myocardial Ischemia ◽  
Protective Effect ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
H9c2 Cells ◽  
Expression Levels ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Low Expression

Myocardial ischemia–reperfusion injury (MIRI) is the leading cause of the poor prognosis for patients undergoing clinical cardiac surgery. Micro-RNAs are involved in MIRI; however, the effect of miR-760 on MIRI and the molecular mechanisms behind it have not yet been described. For our in-vivo experiments, 20 rats were randomly distributed between 2 groups (n = 10): the sham-treatment group and the ischemia–reperfusion (I/R) group. For our in-vitro experiments, H9C2 cells were subjected to hypoxia for 6 h, and then reoxygenated to establish an hypoxia–reoxygenation (H/R) model. High expression levels of of miR-760 were observed in the rats subjected to MIRI and the H9C2 cells subjected to H/R. Further, the levels of lactate dehydrogenase (LDH) and malonaldehyde (MDA) were increased, and the size of the myocardial infarct was notably greater in the rats subjected to MIRI, suggesting that miR-760 worsens the effects of MIRI. The inhibitory effects from NaHS on apoptosis were enhanced, as were the expression levels of cleaved caspase 3 and cleaved PARP in H9C2 cells exposed to H/R, and with low-expression levels of miR-760. TargetScan and dual luciferase reporter assays further confirmed the targeted relationship between dual-specificity protein phosphatase (DUSP1) and miR-760. Additionally, miR-760 overexpression and H/R treatment of H9C2 cells inhibited the expression of DUSP1, which further promoted apoptosis. Furthermore, DUSP1 enhanced the anti-apoptotic effects of NaHS in rats subjected to MIRI. Taken together, these findings suggest that miR-760 inhibits the protective effect of NaHS against MIRI.

scholarly journals The Exosomal lncRNA KLF3-AS1 From Ischemic Cardiomyocytes Mediates IGF-1 Secretion by MSCs to Rescue Myocardial Ischemia-Reperfusion Injury

2021 ◽  
Vol 8 ◽  
Author(s):  
Gecai Chen ◽  
Aihuan Yue ◽  
Meixiang Wang ◽  
Zhongbao Ruan ◽  
Li Zhu
Keyword(s):  
Myocardial Ischemia ◽  
Myocardial Injury ◽  
Cell Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
H9c2 Cell ◽  
H9c2 Cells ◽  
Myocardial Ischemia Reperfusion

The purpose of the study was to explore the mechanism by which myocardial ischemia-reperfusion (I/R) injury-induced exosomes modulate mesenchymal stem cells (MSCs) to regulate myocardial injury. In this study, we established an I/R injury model in vivo and a hypoxia-reoxygenation (H/R) model in vitro. Then, exosomes isolated from H/R-exposed H9c2 cells were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot analysis. CCK-8 assays and flow cytometry were performed to assess cell injury. ELISA was applied to determine the level of insulin-like growth factor 1 (IGF-1). Echocardiography was used to assess cardiac function in vivo. HE staining and TUNEL assays were conducted to analyze myocardial injury in vivo. In the present study, H/R-exposed H9c2 cells induced IGF-1 secretion from MSCs to inhibit cell myocardial injury. Moreover, exosomes derived from H/R-exposed H9c2 cells were introduced to MSCs to increase IGF-1 levels. The lncRNA KLF3-AS1 was dramatically upregulated in exosomes derived from H/R-treated H9c2 cells. Functional experiments showed that the exosomal lncRNA KLF3-AS1 promoted IGF-1 secretion from MSCs and increased H9c2 cell viability. In addition, miR-23c contains potential binding sites for both KLF3-AS1 and STAT5B, and miR-23c directly bound to the 3'-UTRs of KLF3-AS1 and STAT5B. Furthermore, the lncRNA KLF3-AS1 promoted IGF-1 secretion from MSCs and rescued myocardial cell injury in vivo and in vitro by upregulating STAT5B expression. The lncRNA KLF3-AS1 may serve as a new direction for the treatment of myocardial I/R injury.

Abstract 423: Proteasome Priming by Protein Kinase G Protects Against Myocardial Ischemia-reperfusion Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Xuejun Wang ◽  
Erin J Terpstra ◽  
Eduardo Callegari ◽  
Chengjun Hu ◽  
Hanming Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
26S Proteasome ◽  
Transgenic Mouse Line ◽  
Pde5 Inhibition ◽  
Myocardial Ischemia Reperfusion

Cardiac proteasome functional insufficiency is implicated in a large subset of heart disease and has been experimentally demonstrated to play an essential role in cardiac proteotoxicity, including desmin-related cardiomyopathy and myocardial ischemia-reperfusion (I-R) injury. Pharmacological inhibition of phosphodiesterase 5 (PDE5) via sildenafil for example, which can stabilize cGMP and thereby increase cGMP-dependent protein kinase (PKG) activity, is consistently reported to protect against I-R injury; however, the underlying mechanism is not fully understood. We have recently discovered that PKG activation enhances proteasomal degradation of misfolded proteins (Ranek, et al. Circulation 2013), prompting us to hypothesize that proteasome-priming may contribute to cardioprotection-induced by PDE5 inhibition. Here we used a cardiomyocyte-restricted proteasome inhibition transgenic mouse line (Tg) and non-Tg (Ntg) littermates to interrogate the action of sildenafil on I-R injury created by left anterior descending artery (LAD) ligation (30 min) and release (24 hr). Sildenafil was administered 30 min before LAD ligation. Results showed that (1) the 26S proteasome activity of the Ntg I-R hearts was significantly elevated by sildenafil but this elevation was blocked in the Tg line; (2) the infarct size reduction by sildenafil treatment in Ntg mice was completely abolished in the Tg mice with the same treatment; and (3) systolic and diastolic function impairment after I/R was markedly attenuated in sildenafil-treated Ntg mice, but not in the sildenafil-treated Tg mice. Additionally, immunoprecipitation assays show that PKG interacted with the proteasome in cultured cardiomyocytes, and this interaction appeared to be augmented by sildenafil treatment. Moreover, in vitro incubation of active PKG with purified human 26S proteasomes increased proteasome peptidase activities and the phosphorylation at specific serine residues of a 19S proteasome subunit as revealed by “gel-free” nano-LC-MS/MS. We conclude that active PKG directly interacts with, phosphorylates, and increases the activities of, the proteasome and that proteasome priming mediates to cardioprotection of PDE5 inhibition against I-R injury.

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